Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2
AbstractThe oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients. View Full-Text
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Maiuthed, A.; Ninsontia, C.; Erlenbach-Wuensch, K.; Ndreshkjana, B.; Muenzner, J.K.; Caliskan, A.; Ahmed P., H.; Chaotham, C.; Hartmann, A.; Vial Roehe, A.; Mahadevan, V.; Chanvorachote, P.; Schneider-Stock, R. Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2. Cancers 2018, 10, 373.
Maiuthed A, Ninsontia C, Erlenbach-Wuensch K, Ndreshkjana B, Muenzner JK, Caliskan A, Ahmed P. H, Chaotham C, Hartmann A, Vial Roehe A, Mahadevan V, Chanvorachote P, Schneider-Stock R. Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2. Cancers. 2018; 10(10):373.Chicago/Turabian Style
Maiuthed, Arnatchai; Ninsontia, Chuanpit; Erlenbach-Wuensch, Katharina; Ndreshkjana, Benardina; Muenzner, Julienne K.; Caliskan, Aylin; Ahmed P., Husayn; Chaotham, Chatchai; Hartmann, Arndt; Vial Roehe, Adriana; Mahadevan, Vijayalakshmi; Chanvorachote, Pithi; Schneider-Stock, Regine. 2018. "Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2." Cancers 10, no. 10: 373.
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